Monogenic forms of diabetes mellitus: an update.

There are several monogenic disorders of pancreatic β-cell function, characterized by various degrees of chronic hyperglycemia. They are usually diagnosed early in life, in neonates or during infancy, in childhood and even in young adulthood1-3. The identification of causal mutations in a dozen of different genes has already proven to have a great clinical impact opening new avenues in genomic medicine and pharmacogenetics4,5. These diseases comprise a broad spectrum of diabetic phenotypes including neonatal diabetes mellitus, non auto-immune diabetes in infancy, dominantly inherited forms of early-onset diabetes (also named Maturity-Onset Diabetes of the Young [MODY], and first recognised by Tattersall in 1975) and very rare diabetes-associated syndromes1-3,6. Both Neonatal Diabetes Mellitus (NDM) and Monogenic Diabetes of Infancy (MDI, as diabetes may be silent in the first couple of months of life) are rare (∼1:300,000 live births) but potentially devastating diseases as causing low, or even undetectable levels of insulin2,3. Two forms are recognized on clinical grounds, either transient (TNDM) or permanent (PNDM), which differ in the duration of insulin dependence early in the disease, and to some extent in their genetic and molecular origins2,3 (fig. 1). In most instances, early-infancy diabetes is unrelated to auto-immunity3. NDM/MDI are indeed genetically heterogeneous disorders mainly caused by heterozygous mutations in KCNJ11, ABCC8 and INS genes7-10. Rarer genetic aetiologies which may include extra-pancreatic features have been reported, including recessive mutations in IPF1 (causing pancreas agenesis and exocrine pancreatic insufficiency), PTF1A (in association with cerebellar hypoplasia), GLIS3 (in association with congenital hypothyroidism) and in EIF2AK3 (causing Wolcott Rallison syndrome)1-3. The MODY subtype, a group of clinically heterogeneous, often non-insulin-dependent forms of diabetes, usually develops in childhood or in thin young adults (before age 25 years) and may represent 1-2% of all diabetes cases1,6. So far, heterozygous mutations or chromosome rearrangements in seven genes have been identified as responsible for MODY (fig. 2). These genes encode the enzyme glucokinase (GCK, MODY2), the transcription factors hepatocyte nuclear factor-4α (HNF4A, MODY1), hepatocyte nuclear factor-1α (HNF1A, MODY3), insulin promoter factor-1 (IPF1, MODY4), hepatocyte nuclear factor-1β (HNF1B, MODY5) Diabetes mellitus hoy